权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Elucidating the Mechanism of Amyloid Formation by Human Lysozyme

阐明人溶菌酶形成淀粉样蛋白的机制

基本信息

批准号：
BB/E019927/1
负责人：
Christopher Dobson
金额：
$ 73.1万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2007
资助国家：
英国
起止时间：
2007 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FE019927%2F1
关键词：
Elucidating Mechanism Amyloid Formation Human

项目摘要

Our bodies contain some 100,000 proteins that enable or regulate essentially every chemical or biochemical process on which our lives depend. Under normal circumstances these proteins remain in their soluble functional states, but under other circumstances, for example as a result of mutations or even the impairment of regulating processes, they can form large insoluble aggregates that are non-functional and even toxic. This process is of great importance because it is the underlying origin of a range of debilitating human disorders, including neurodegenerative conditions such as Alzheimer's disease, the transmissible spongiform encephalopathies (such as CJD, the human analogue of 'mad cow disease'), type 2 (late onset) diabetes and systemic pathologies in which large quantities, sometimes kilograms, of protein are deposited in vital organs such as the kidney, heart and liver. In each of these diseases, a single protein undergoes a structural transition, often resulting in the formation of thread-like aggregates known as amyloid fibrils. Many of these diseases are linked to the ageing process, and as a large fraction of the world's population lives to ages unprecedented in human history, these diseases are emerging as among the most feared and debilitating in the modern world. In recent years, much research has focused on understanding what causes proteins to misfold and form amyloid structures, and on the specific mechanism by which such transitions occur. Nevertheless, as a result of structural heterogeneity, low populations and a transient nature, obtaining detailed information about this process has presented a formidable challenge. The primary objective of this study is to elucidate structural information of the different species that are populated along the aggregation pathway of human lysozyme. As well as being associated with a systemic amyloid disorder, lysozyme is one of the most highly studied of all proteins providing a unique opportunity to probe the difference between normal and aberrant behaviour at atomic resolution. By studying species populated under fibril forming conditions, we will be able to begin to understand not only the structures of intermediate species, but also the dynamics of the conversion between the different states involved in fibril formation. These studies should generate a sufficiently profound understanding of the distinctive differences between species involved in normal and aberrant folding behaviour to contribute significantly to the identification of novel strategies through which rational therapeutic intervention could lead to prevention or treatment, not just of this specific disease, but also perhaps the entire family of protein misfolding disorders.

我们的身体含有大约 100,000 种蛋白质，这些蛋白质基本上能够实现或调节我们生命所依赖的每一种化学或生化过程。在正常情况下，这些蛋白质保持可溶的功能状态，但在其他情况下，例如由于突变甚至调节过程受损，它们可以形成大的不溶性聚集体，这些聚集体无功能甚至有毒。这一过程非常重要，因为它是一系列使人衰弱的人类疾病的根本根源，包括神经退行性疾病，如阿尔茨海默氏病、传染性海绵状脑病（如克雅氏病，人类类似的“疯牛病”）、2 型（迟发性）糖尿病和系统性病变，其中大量（有时是公斤）的蛋白质沉积在生命体中。肾脏、心脏和肝脏等器官。在每种疾病中，单个蛋白质都会经历结构转变，通常导致形成称为淀粉样原纤维的线状聚集体。其中许多疾病与衰老过程有关，并且由于世界上很大一部分人口的寿命达到了人类历史上前所未有的年龄，这些疾病正在成为现代世界最令人恐惧和最令人衰弱的疾病之一。近年来，许多研究都集中在了解导致蛋白质错误折叠并形成淀粉样蛋白结构的原因，以及发生这种转变的具体机制。然而，由于结构异质性、人口少和短暂性，获取有关这一过程的详细信息提出了巨大的挑战。本研究的主要目的是阐明沿着人类溶菌酶聚集途径分布的不同物种的结构信息。除了与系统性淀粉样蛋白疾病相关之外，溶菌酶还是所有蛋白质中研究最深入的蛋白质之一，为在原子分辨率下探究正常行为和异常行为之间的差异提供了独特的机会。通过研究在原纤维形成条件下繁殖的物种，我们不仅能够开始了解中间物种的结构，而且能够了解原纤维形成所涉及的不同状态之间转换的动态。这些研究应该对涉及正常和异常折叠行为的物种之间的独特差异产生足够深刻的理解，从而极大地有助于识别新策略，通过这些策略，合理的治疗干预可以导致预防或治疗，不仅是这种特定的疾病，而且可能是整个蛋白质错误折叠疾病家族。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Protein amyloids develop an intrinsic fluorescence signature during aggregation.

DOI：
10.1039/c3an36798c
发表时间：
2013-04-07
期刊：
The Analyst
影响因子：
0
作者：
Chan FT;Kaminski Schierle GS;Kumita JR;Bertoncini CW;Dobson CM;Kaminski CF
通讯作者：
Kaminski CF

Analysis of the native structure, stability and aggregation of biotinylated human lysozyme.

生物素化人溶菌酶的天然结构、稳定性和聚集分析。

DOI：
10.17863/cam.49123
发表时间：
2012
期刊：
影响因子：
0
作者：
Ahn M
通讯作者：
Ahn M

The Significance of the Location of Mutations for the Native-State Dynamics of Human Lysozyme

突变位置对人类溶菌酶天然状态动力学的意义

DOI：
10.17863/cam.7014
发表时间：
2016
期刊：
影响因子：
0
作者：
Ahn M
通讯作者：
Ahn M

Methods and models in neurodegenerative and systemic protein aggregation diseases.

神经退行性和全身性蛋白质聚集疾病的方法和模型。

DOI：
10.2741/3626
发表时间：
2010
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
0
作者：
Brorsson AC
通讯作者：
Brorsson AC

The Significance of the Location of Mutations for the Native-State Dynamics of Human Lysozyme.

DOI：
10.1016/j.bpj.2016.10.028
发表时间：
2016-12-06
期刊：
BIOPHYSICAL JOURNAL
影响因子：
3.4
作者：
Ahn, Minkoo;Hagan, Christine L.;Bernardo-Gancedo, Ana;De Genst, Erwin;Newby, Francisco N.;Christodoulou, John;Dhulesia, Anne;Dumoulin, Mireille;Robinson, Carol V.;Dobson, Christopher M.;Kumita, Janet R.
通讯作者：
Kumita, Janet R.